Ivabradine or 3-[3-({[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}(methy)amino)propyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2-one has the formula (I)
and is used in cardiology for heart failure, hypertension, angina and post-infarction treatment.
Ivabradine is therefore in an enantiomeric form, in particular in the (S) form. The most common synthesis of ivabradine entails condensation between the compounds (II) and (III) shown in the following diagram:
in which R is hydrogen or methyl and Hal is an atom of halogen.
Preparation of the intermediate amine (III) in enantiomerically pure form is the subject of numerous patents.
EP 0 534 859 describes preparation of the compound (III) in which R is methyl, by means of a resolution with camphorsulphonic acid with a yield of 2-3% while EP 1 598 333 describes resolution of the compound (III) in which R is hydrogen with N-acetyl-L-glutamic acid, obtaining better yields. Although said process produces good yields, it must be performed controlling the operating conditions accurately and carefully both during its use as a resolving agent and during its recovery and re-use, since the N-acetyl-L-glutamic acid can give rise to intramolecular reactions, degrading and therefore no longer being available as a reagent for the resolution.